A plurality of mesenchymal stem cell (MSC) related products, for clinical use, are known and more products are in development and are expected to be approved for human use in the future. MSCs exhibit some immuno-modulatory properties, which can contribute to their therapeutic value, and MSCs are used, inter alia, for treatment of autoimmune diseases. The immunosuppressive potential of human MSCs is evidenced for example by studies showing the inhibitory effects on the proliferation of T-cells, B-cells, dendritic cells and natural killer cells (Han et al., 2012).
EP 1795588 describes use of adipose tissue derived MSCs for treatment of graft versus host disease (GVHD); the cells are said to exert immunosuppressive properties.
EP 2545928 relates to MSC-containing cell preparations whose immunosuppressive ability is maintained by means of serum-free or low serum culture.
WO 2012/111997 discloses a combination therapy in which MSCs are given with immunoregulatory T cells, to achieve suitable immunosuppression for the MSC-based therapy.
WO 2009/1105624 discloses compositions and methods relating to the co-delivery of a molecule and a polypeptide to cells to improve the therapeutic efficacy of the molecules. Delivery of growth factors is improved by co-delivering these growth factors with their receptors and co-receptors; such as syndecans 1, 2, 3 and 4. Co-delivery of syndecans with growth factors protects the growth factors from proteolysis, enhances their activity, and targets the growth factors to the cell surface to facilitate growth factor signalling.
KR1020100106744 relates to a composition for preventing or treating migratory dermatitis or melanogenesis-associated diseases. The composition for preventing or treating migratory dermatitis contains syndecan-2 as an active ingredient. The migratory dermatitis conditions considered are melanoma, hyperpigmentation, hypopigmentation or vitiligo.
WO 02/087609 relates to a pharmaceutical composition for preventing papillomavirus infection in a mammal comprising, a soluble peptide, protein, or fusion protein that binds to papillomavirus particles as a ligand for syndecans having heparan sulfate glycosaminoglycan chains attached.
WO 03/062386 relates to methods and materials related to modulating syndecan levels and angiogenesis in an animal. Syndecan polypeptides and nucleic acids encoding syndecan polypeptides are disclosed. These are used to produce polynucleotides and polynucleotide analogues for modulating angiogenesis. Methods for identifying syndecan- and angiogenesis-modulating agents are also discussed.
Mukhopadhyay, A. et al., J. Trauma Injury Infect. Crit. Care, 2010, vol. 68, pp. 999-1008 concludes that syndecan-2 and FGF-2 may interact with each other, resulting in the shedding of syndecan-2 from cells and which in turn activates events responsible for a keloidic phenotype.
Kaur, C. et al., Glia, 2009, vol. 57, pp. 336-349, examines syndecan-2 expression in the amoeboid microglial cells and notes that this is up-regulated by hypoxia.
Contreras, H. R. et al., Biochem. Biophys. Res. Comm., 2001, vol. 286, pp. 742-751, examines syndecan-2 expression in cancer, and notes that syndecan-2 expression is involved in differentiation of certain cells towards a migratory mesenchymal-like phenotype.
Sojoong Choi, et al., Biochem. Biophys. Res. Comm., 2012, vol. 417, pp. 1260-1264, examined the role of matrix metalloproteinase-7 (MMP-7) on shedding of syndecan-2 from colon cancer cells. It was observed that MMP-7 directly mediates shedding of syndecan-2 from these cells.
Alexopoulou, A. N. et al., BMC Cell Biol., vol. 9, 2008, doi:10:10.1186/1471-2121-9-2 investigated vectors useful for the long term expression of transgenes during stem cell differentiation towards mesoderm. One of the vectors used encodes syndecan-2.
WO 2011/153458 discloses a method of interfering with dengue infection comprising interfering with dengue virus binding to a syndecan present on a cell targeted by dengue virus. Also disclosed are pharmaceutical compositions relating to this purpose.
Mytilinaiou, M. et al., IUBMB Life, 2013, vol. 65, pp. 134-143 examined the role of syndecan-2 as a regulator of cellular adhesion of fibrosarcoma cells that is mediated by TGFβ2/Smad2.
Kim, Y. et al., Oncogene (2003), vol. 22, pp. 826-830 observed that reduced syndecan-2 expression correlates with trichostatin-A-induced morphological changes and reduced tumorigenic activity in colon carcinoma cells. In addition downregulation of syndecan-2 expression by antisense cDNA mimicked the morphological changes and reduced anchorage-independent growth of colon cancer cells.
Chung, H. et al., Journal of Biological Chemistry, vol. 287, no. 23, pp. 19326-19335, 2012, found that melanocortin 1 receptor regulates melanoma cell migration by controlling syndecan-2 expression. This is because melanocortin 1 receptor inhibits activation of p38 MAPK, subsequently enhancing syndecan-2 expression and migration in melanoma cells.
Péterfia, B. et al., PLoS ONE, vol. 7, no. 6, e39474, observed that syndecan-1 enhances malignancy of a mesenchymal tumour cell line, via induction of syndecan-2 expression. Thus, syndecan-1 enhances proliferation, migration and metastasis of human fibrosarcoma cell-line cells in cooperation with syndecan-2.
Ruiz, X. et al., PLoS ONE, vol. 7, no. 8, e43049, describe their findings that syndecan-2 is a novel target of insulin-like growth factor binding protein-3 (IGFBP-3) and that syndecan-2 is over-expressed in fibrosis. The increased SDC2 expression is due, at least in part, to the activity of two pro-fibrotic factors, TGFβ and IGFBP-3.
Dieudonné, F-X et al., Journal of Bone and Mineral Research, vol. 27, no. 10, pp. 2118-2129, describe how syndecan-2 expression is upregulated by doxorubicin in osteosarcoma cells. T-cell factor (TCF) is responsible for inhibition of syndecan-2. Thus, targeted inhibition of TCF activity promotes syndecan-2 expression and sensitization to doxorubicin in osteosarcoma cells and bone tumours in mice.
KR 20120013915 describes a composition for diagnosing colon cancer containing an agent for measuring expression level of syndecan-2 peptide fragments. The agent contains an antibody which is specific to a syndecan-2 peptide fragment.
Huang, X. et al., Oncology Reports 2009, vol. 21, pp. 1123-1129, discusses the prognostic significance of altered expression of syndecan-2 (SDC2) and cysteine-rich 61 (CYR61) in oesophageal squamous cell carcinoma.
A common problem in the art is that there is insufficient immunosuppression for MSC-based products to be used on their own or that the immunosuppressive properties of the MSCs are lost, i.e. not maintained, over time in cell culture passage. It is desirable to retain, stimulate or to be able to recover these properties.
Immunosuppressive regimens can be used to prevent or reduce transplant rejection, and clinically used immunosuppressive regimens typically include a combination of several agents used concurrently. It is desirable to identify alternative immunosuppressive agents and therapies. Similarly, it is desirable to identify agents and therapies that promote angiopoiesis. Further, it is desirable to be able to assay the potency of potential therapeutic products in this field. A proposed assay is based upon soluble TNFR1 but alternative and preferably improved assays are needed.